Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis by Jae-Seung Moon 1,2,11, Shady Younis 1,2,3,11, Nitya S. Ramadoss1,2, instant download

Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis by Jae-Seung Moon 1,2,11, Shady Younis 1,2,3,11, Nitya S. Ramadoss1,2, instant download

The immune mechanisms that mediate synovitis and joint destruction inrheumatoid arthritis (RA) remain poorly defined. Although increased levels ofCD8+ T cells have been described in RA, their function in pathogenesis remainsunclear. Here we perform single cell transcriptome and T cell receptor (TCR)sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies(ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing largeclonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprisessmaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC classI activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxicmediators, and mediate killing of target cells. We also demonstrate that theseclonally expandedGZMB+CD8+ cells are present in RA synovium. These findingssuggest that cytotoxic CD8+ T cells targeting citrullinated antigens contributeto synovitis and joint tissue destruction in ACPA+ RA.